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How can we make cancer treatment less toxic?

The answer is in your genetic code

Initial findings from a pilot study using 100,000 Genomes Project data may help doctors to decide which dose of medications are the most appropriate for different cancer patients to take.

Medicines can affect people in different ways – a drug might work really well in some people, but not work or even cause serious side effects (‘adverse reactions’) in others. Genetic differences between people are behind some of these different reactions to drugs. The study of these genetic differences is called ‘pharmacogenomics’. Knowing about pharmacogenomics can be very important in deciding which medications a patient should take.

The DPYD gene controls the process that breaks down many medicines in the liver so that they can then be safely excreted by the body. There is strong evidence that four variants in the DYPD gene increase the risk that a patient will suffer severe or fatal toxic side effects when treated with a type of drug called fluoropyrimidines. These drugs are commonly prescribed to patients with breast or colorectal cancer and include capecitabine or 5-Fluorouracil.

If a patient has one of these four variants of DPYD, these drugs are not broken down as well allowing them to build up to toxic levels in the liver. Published guidelines suggest that patients with these genetic variants should receive reduced doses of capecitabine or 5-Fluorouracil, or avoid the drugs completely in order to prevent toxic side effects. However this is not yet routinely done.

As part of the pilot, whole genome sequence (WGS) data from all cancer participants within the Project is now being analysed for the presence of these four DPYD gene variants. The findings are then being made available to Genomic Medicine Centres. If clinicians know that a patient has one or more copies of one of these variants, they will be able to assess whether adjusting therapy regimens may reduce the risk of toxicity. Feedback on the action taken by the clinician will be recorded and analysed to help determine the clinical effectiveness of analysing these variants within the NHS. This demonstrates how whole genome sequencing can be used to ensure that patients get the most effective and least toxic medicines for their cancer.

Find out more about the variants being assessed in the cancer analysis technical document here.

There is NHSE published guidance for clinicians on validation and reporting of DPYD variants available here.